tbuckley/cabot-search huggingface dataset:
PB1757: VARIANT PHILADELPHIA CHROMOSOME IN ALL
Authors: N. Bouayed Abdelmoula, B. Abdelmoula, A. Sbai, M. Ben ayed, S. Aloulou
Journal: HemaSphere (2022)

Background: The Philadelphia chromosome (Ph) is detected in 10–20% of adult patients with B-cell acute lymphoblastic leukemia (B-ALL). At the cytogenetic level, it usually arises from the balanced (9;22)(q34;q11) translocation. In 50–70% of the Ph-positive ALL patients, the BCR gene breaks between exons 1 and 2, known as m-bcr region. The BCR-ABL chimeric gene encodes the p190 fusion protein. In approximately 5% of these patients, the Ph originates through other rearrangements than the classic t(9;22). These variant translocations involve others chromosomes in addition to chromosomes 9 and 22. Aims: To contribute to the description of patients’ clinical characteristics and prognosis with variant Ph chromosome-positive leukemia, we report a Ph chromosome-positive ALL characterized by an unusual variant Ph chromosome. Methods: A 34-year-old woman with B-ALL was assessed at the genetic level. Cytogenetic and molecular exploration were conducted using bone marrow and blood samples. Cytogenetic analysis was performed on lymphocytes and bone marrow cells. The cells were treated with colchicine and hypotonic KCl solution. The pellet was fixed and washed in methanol-acetic acid (3:1). The cells were resuspended in fixative and dropped onto slides. Chromosome-banding analysis was performed using RHG and GTG banding techniques. Three karyotypes and 25 metaphases were analyzed according to the International System for Human Cytogenetic Nomenclature. Multiplex reverse transcription-PCR (RT-PCR) was used to identify the BCR-ABL transcript. RT-PCR was performed according to European recommendations, as described previously. Results: Cytogenetic analysis showed 45 chromosomes with a masked variant Ph translocation: 45,XX,der(9)t(9;20;22)(q34;q?,q11), der(20) t(9;20;22)(q34;q?,q11),-20,-22. At the molecular level, the patient’s BCR-ABL fusion gene was confirmed as e1a2 transcript. FISH procedures were performed using an bcr-abl probe that showed a double fused gene signal on interphase nuclei. Summary/Conclusion: Unrelatedly to age and breakpoint location, Ph-positive ALL are characterized by poor prognosis. A unique case of similar complex chromosome 9, 20, and 22 rearrangements in acute lymphoblastic leukemia has been reported. This variant Ph chromosome involving three chromosomes was associated with two markers leading to a duplication of BCR and ABL sequences. Further FISH analysis using the whole chromosome 9, 20 and 22 painting probe will be significant to delineate the complex chromosomal rearrangement involved in our B-ALL case.
PB2058: IMPACT OF COMORBIDITIES AND RESPONSE TO TREATMENT ON THE MPN SAF ASSESSMENT OF PHILADELPHIA CHROMOSOME NEGATIVE MYELOPROLIFERATIVE SYNDROMES.
Authors: B. Mohamed, H. Asma, R. Amina, S. A. Nadjet, Z. Zahia
Journal: HemaSphere (2022)

Background: Ph chromosome negative myeloproliferative syndromes (MPN) are a heterogeneous group of hematological malignancies including essential thrombocythemia (ET), polycythemia (PV) and primary myelofibrosis (PMF). The MPN SAF or MPN 10 (Myeloproliferative Neoplasm Symptom Assessment Form) questionnaire is a validated tool for assessing the symptoms presented by patients with MPN, and their evolution during treatment. Aims: To assess the impact of comorbidities and response to treatment on the symptomatology of patients with MPN assessed by MPN SAF. Methods: This is a study carried out in our hematology department, which involved patients monitored and treated for MPN. We used the MPN SAF questionnaire wich includes 10 items, rated from 0 to 10, in relation of the MPN symptoms burden. Comorbidities were assessed using the CIRS score (Cumulative Illness Rating Scale). Statistically, ANOVA and log rank tests were used to study the impact of comorbidities and response to treatment on MPN SAF score. The tests are significant if p < 0.05. Results: 67 patients participated in this study, 31 women and 36 men, with a median age of 65 years [22-86]. 36 (54%) patients had PV, 25 (37%) ET, and 6 (9%) PMF. 16 (24%) patients had splenomegaly, bulky in half. The mean MPN SAF score was higher in patients with PMF (47) than in those with ET (26) or PV (21) (p=0.04). 43 (64%) patients had at least one associated disease, with a CIRS ≥ 6 in 17 (25%). The MPN SAF score was well correlated with the comorbidity score of the patients (p<0.001): patients with CIRS < 6 had a mean MPN score of 48 vs 18 in patients with CIRS ≥ 6. Depending on the response to treatment and disease control, the MPN SAF score was higher in patients refractory to treatment (mean: 35), compared to those with complete or partial remission (17, 22 respectively, p=0.02). Summary/Conclusion: Our study concludes to a worsening of MPN symptoms when associated to comorbidities. It is very likely that associated diseases maintain a chronic inflammatory state, which is added to that of chronic myeloid neoplasia, mainly when it is refractory to treatment.
PB2066: THE STUDY OF GSTP1 AND MDR1 GENES POLYMORPHISMS IN HODGKIN’S LYMPHOMA AND THEIR LINK WITH CHEMOTHERAPY RESPONSE.
Authors: M. Voytko, Y. Shebunyaeva, O. Goreva, T. Pospelova, A. Grishanova, V. Vavilin
Journal: HemaSphere (2022)

Background: Glutathione-S-transferase P1 and ATP-dependent transporter P-glycoprotein are enzymes of the second phase of xenobiotic metabolism that participate in biotransformation of agents of standard protocol of Hodgkin’s Lymphoma chemotherapy. The polymorphism of the GSTP1 and MDR1 genes encoding these proteins causes changes in their activity, which can provide an individual patients’ response to chemotherapy. In this regard, the search for predictive genetic factors for the effectiveness of antitumor therapy is an important task. Aims: to demonstrate the association between polymorphic variants of GSTP1 (A313G, C341T) and MDR1 (C1236T, G2677T, C3435T) genes in patients with Hodgkin’s lymphoma. Methods: Overall, 77 Hodgkin’s lymphoma patients aged 18-74 years who were treated by BEACOPP and ABVD chemotherapy protocols in Oncohematological Departments of City Clinical Hospital №2 and Novosibisk State District clinical Hospital were enrolled in this study. The effectiveness of chemotherapy was evaluated after 4-6 cycles of chemotherapy in accordance with clinical guidelines. Depending on the achieved results of treatment, all patients were divided into two groups: patients with complete/partial remission and patients with progressive/refractory or relapsed lymphoma. Polymorphisms of GSTP1 (A313G, C341T) and MDR1 (C1236T, G2677T, C3435T) genes were defined by PCR method with real-time detection in the samples of peripheral blood in the Centre of Collective Usage «Proteomic analysis» FRC FTM. The odds ratio (OR) used to evaluate the link between genotypes with efficacy of chemotherapy. Results: We found the following frequencies of mutant alleles in Hodgkin’s Lymphoma patients: GSTP1313G – 31.17%, GSTP1 341T – 9.7%, MDR1 1236T – 50.00%, MDR1 2677T – 48.70%, MDR13435 ТОНН – 58.44%. Patient’s genotypes were similar to described genotypes of healthy Europeans. There was no significant difference in distribution of frequency alleles and GSTP1 A313G (χ2=0,89, p=0,34), GSTP1 C341T (χ2=0,11 R=0,74), MDR1 C1236T (χ2=0,01, p=0,93), MDR1 G2677T (χ2=0,37, p=0,54), MDR1 C3435T (χ2=0,01, р=0,97) genotypes between group of Hodgkin’s lymphoma patients with complete/partial remission and group with progressive/refractory or relapsed lymphoma. At the same time we found the significant correlation between GSTP1 A313G heterozygotes and formation of progressive/refractory and prolapsed course of disease (OR = 10.80; CI 95% = 1.23 – 496.52). There was no significant association between efficacy of chemotherapy and other studied genotypes, namely GSTP1 C341T, MDR1 C1236T, MDR1 G2677T, MDR1 C3435T genotypes. Summary/Conclusion: The observed correlation between GSTP1 A313G gene polymorphisms and formation progressive/refractory or prolapsed course of disease needs to be studied to provide safe and effective specific chemotherapy.
PB2183: RELAPSE PREDICTS POOR OUTCOMES IN FLT3-MUTATED ACUTE MYELOID LEUKEMIA POST ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION
Authors: E. Gavriilaki, A. Papalexandri, D. Mallouri, I. Batsis, A. Vardi, Z. Bousiou, C. Demosthenous, A. Panteliadou, N. Spyridis, G. Karavalakis, T. Touloumenidou, M. Masmanidou, G. Pistiolas, F. Mouladeniou, C. Vadikoliou, C. Lalayanni, E. Yannaki, A. Anagnostopoulos, I. Sakellari
Journal: HemaSphere (2022)

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative option for patients with FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplication) acute myeloid leukemia (AML). Although sorafenib has been recommended as maintenance treatment, data on risk factors and outcomes in these patients are limited. Aims: We investigated the risk factors and outcomes in patients with FLT3-mutated AML that underwent alloHCT. Methods: We enrolled consecutive adult patients with FLT3-mutated AML that underwent alloHCT at our JACIE-accredited center over the last two decades based on EBMT standards. The following factors were recorded and analyzed: age, disease, phase at transplant, type of donor and transplant, grade II-IV acute and moderate/severe chronic graft-versus-host disease (GVHD), relapse, treatment-related mortality (TRM), disease-free (DFS) and overall survival (OS). Results: We studied 43 patients with FLT3-mutated AML who received alloHCT at a median age of 45 (18-62) years from sibling (21), matched (16) or mis-matched (3) unrelated, and haploidentical donors (3). Phase at transplant was first complete remission/CR1 (31 patients), CR2 (9) or relapsed/refractory disease (3). With a median follow-up of 26.5 (1.2-239) months, relapse was observed in 16 patients, 4 of whom presented only with isolated extramedullary disease. Five-year cumulative incidence (CI) of relapse was 41.7% and was independently associated with previous lines of treatment (p=0.015), disease phase at transplant (25.7% for CR1, 50% for CR2, and 100% for relapsed/refractory disease, p=0.007), and chronic GVHD (p=0.004). Relapse was treated with chemotherapy (15 patients), donor lymphocyte infusions (7), azacytidine (6), or gilteritinib (3). No patient received sorafenib either as maintenance or treatment. Only one relapsed patient survived after treatment of isolated extramedullary disease. Five-year CI of TRM was 17.4% and was associated only with disease phase at transplant (p<0.001). Five-year DFS and OS were 46.5% and 52.5%, respectively. The only significant predictor of OS was relapse (beta=0.303, p<0.001). Summary/Conclusion: r study confirms that relapse post alloHCT is an imminent feature of FLT3-mutated AML, associated with poor outcomes. Disease phase at transplant is an important risk factor for alloHCT outcomes. Nevertheless, relapse incidence remains high, even in patients transplanted in CR1, highlighting the necessity of maintenance therapy with FLT3 inhibitors.
P1325: ACCURACY OF CRYOTUBE METHOD TO ASSESS PRETHAWING RICHNESS OF CRYOPRESERVED CD34+ HEMATOPOIETIC STEM CELLS FOR AUTOLOGOUS TRANSPLANTATION
Authors: D. Belloumi, I. Ben Yaiche, J. Fekih, A. Ghorbel, L. Torjemane, M. Chaabane, S. Mekni, N. Ben Abdeljelil, I. Turki, S. Ladeb, S. Hmida, T. Ben Othman
Journal: HemaSphere (2022)

Background: Cryopreservation of hematopoietic stem cells (HSC) is associated with variable loss of CD34+ graft richness. Aims: Our aim was to examine the validity of measuring CD34 richness on flow cytometry from cryotubes before thawing infusing bags in order to reduce risks associated with low-quality grafts. Methods: CD34+ cells richness was analyzed on flow cytometry in leukapheresis procedures before freezing and after thawing. Data from control cryotubes were compared to those from infusing bags using Wilcoxon signed-rank test. Results: Between October 2017 and November 2020, 129 patients underwent HSC autologous transplantation in our department for multiple myeloma (n=94) or Hodgkin and non-Hodgkin lymphoma (n=35). The mean time from mobilization to HSC transplantation was 3.3 months (0-11).The median age was 52 years (11-66) with a sex ratio of 1.4. We analyzed 154 infusion bags. The mean amount of CD34+ cells on flow cytometry was respectively 3.2 x 10⁶/kg (0.39-19.95) and 1.86 x 10⁶/kg (0.16-21.58) per bag before cryopreservation and after thawing, corresponding to a cell loss of 40% (p=0.008). The mean CD34+ cell richness found in cryotubes after thawing was 1.7x 10⁶/kg (0-21.09), concordant with that found in the infusing bags after thawing (p=0.132). The positive predictive value (PPV) of cryotubes (CD34+ cells richness in infusing bag greater than 2 x 10⁶/kg when cryotube richness is greater than 2 x 10⁶/kg) was 70% and the negative predictive value (NPV) was 71%. Cryopreservation duration >3 months did not alter the predictive value of cryotubes (PPV=71%, NPV=68%). The PPV was lower for patients older than 50 years (60%) and for patients treated for lymphoma (50%) compared to those younger than 50 years (82%) and treated for multiple myeloma (75%). No delayed engraftment was noted in our cohort regardless of CD34+ richness in the cryotube. Summary/Conclusion: Cryotube used to evaluate CD34+ richness prior to reinfusion is not informative enough although its predictive value may differ according to the age and the underlying disease.
Abstract LB136: Characterization of a novel PI3Kinase inhibitor for treatment of glioblastoma multiforme
Authors: Ekokobe Fonkem, M. Karen Newell-Rogers, Richard Tobin, Debbie Healey, Mita Das, Sara Bowen, Chad Quarles, John Clark
Journal: Cancer Research (2022)

Abstract The purpose of this study was to test the effects of a novel small molecule inhibitor of phosphatidylinositol-3 kinase (PI3K) for the treatment of glioblastoma multiforme (GBM). The key hurdles to effective treatment for GBM, the “most deadly” form of brain cancer, are resistance to chemotherapy, to radiation, and to immune check point inhibitor therapy. The overarching goal of our experiments has been to determine if a well-characterized small molecule inhibitor of PI3K, GCT.Glio.1, would improve treatment outcomes for GBM patients. The PI3K pathway has been shown to confer both chemotherapy and radiation resistance in GBM. GCT.Glio.1 (NPT520-337), a small molecule compound known to cross the blood brain barrier (BBB), was developed to target PI3K to treat GBM. GBMs, like other “difficult to treat” tumors, often over-express and actively utilize the PI3K pathway for survival, cell growth, and cell division. We used this small molecule inhibitor to determine how targeting the PI3K pathway impacts treatment resistance in GBM. We hypothesized that targeting PI3K would result in growth arrest, increase cell surface expression of a key immune check-point inhibitor target PD-L1, and would sensitize the GBM to treatment with radiation. Treatment of GL261 mouse GBM and U251 human GBM cell lines with GCT.Glio.1 resulted in profound growth arrest at the G2/M checkpoint, increased the cell surface expression of PD-L1, and synergized with radiation to cause growth arrest and subsequent cell death. In conclusion, these results indicate that GCT.Glio.1 may be a strong candidate for treatment of GBM, and suggest that GCT.Glio.1 is a candidate for rationally designed combinations with currently available radiation and immune checkpoint inhibitor therapies. Currently, the animal studies using GCT.Glio.1 in the GL261 mouse model of GBM have been initiated. Based on our promising pre-clinical data and early encouraging results from pre-clinical pharmacology and safety studies, we anticipate filing a pre-Investigational New Drug application (pre-IND) as the next step toward our goal of a clinical trial using GCT.Glio.1 for GBM patients. Citation Format: Ekokobe Fonkem, M. Karen Newell-Rogers, Richard Tobin, Debbie Healey, Mita Das, Sara Bowen, Chad Quarles, John Clark. Characterization of a novel PI3Kinase inhibitor for treatment of glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB136.
Abstract SY30-03: Colorectal cancer screening in underserved populations: COVID, silver linings, and challenges ahead
Authors: Maria Elena Martinez
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) screening and appropriate follow-up can reduce incidence and mortality, but screening and abnormal test follow-up rates are suboptimal among medically underserved populations. The United States Preventive Services Task Force (USPSTF) recommends CRC screening through a variety of invasive and noninvasive tests for adults aged 50 to 75 years (grade A) and for individuals aged 45 to 49 years (grade B). Evidence-based interventions and other strategies exist to promote CRC screening, but adoption and implementation of these are limited, especially among medically underserved individuals and those receiving care at community health centers (CHCs) in the United States. Aside from low screening uptake, low colonoscopy follow-up of abnormal stool tests is common in CHCs, estimated to be approximately 50%. Lack of colonoscopy completion for abnormal stool tests defeats the purpose of screening because early-stage cancers go undetected, resulting in higher CRC mortality. Reasons for lack of colonoscopy completion are poorly understood. Cancer screening rates have plummeted as a result of the coronavirus disease 2019 (COVID-19) pandemic, resulting in an estimated 10,000 deaths from breast and CRC alone in the U.S. over the next 10 years. The impact of this drop specific to racial/ethnic groups and communities facing barriers prior to the pandemic is unknown. Prior to the onset of the pandemic, the National Cancer Institute invested in CRC screening research as a result of the Cancer Moonshot’s Blue Ribbon Panel recommendation through its Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) initiative. ACCSIS supports research to build the evidence base on multilevel interventions to increase CRC screening, follow-up, and referral to care. Five ACCSIS research projects and a 3-site American Indian project are supported through this initiative, all focusing on underserved populations across the US. This presentation will provide an overview of the key components of the ACCSIS program, challenges faced resulting from the pandemic, and opportunities for overcoming these. In its 2022 report, the President’s Cancer Panel called for equitable cancer screening as a top public health priority. The report emphasizes that overcoming barriers to CRC screening and follow-up among underserved populations must be addressed to ensure that the benefits reach all populations. This provides a timely opportunity to address the extraordinary CRC screening challenges and disparities faced by vulnerable populations. Citation Format: Maria Elena Martinez. Colorectal cancer screening in underserved populations: COVID, silver linings, and challenges ahead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY30-03.
PB1859: DEFINING T-CELL POPULATIONS IN CHRONIC LYMPHOCYTIC LEUKAEMIA
Authors: A. Mora, P. Jara, M. Argüello, N. Albiol, J. Sierra, M. E. Moga, C. Moreno
Journal: HemaSphere (2022)

Background: Chronic Lymphocytic Leukaemia (CLL) is a B-cell lymphoproliferative disorder in which the survival of leukemic cells highly depends on the tumour microenvironment. Indeed, abnormalities in the T-cell compartment have been described many years ago although their role role in supporting or controlling leukemic cells is still unclear. More recently, some studies suggested that pathway inhibitors including BTKi (i.e., ibrutinib) may act as immunomodulatory drugs by restoring at least in part the T-cell compartment and other immune circulating cells. Aims: We aimed to further characterize the differentiation and maturation status and in vitro activation capability of T-cells at different stages of CLL (stable and progressive) and to analyze the changes induced on these cells by the BTKi Ibrutinib given as single agent in patients who were in clinical response. Methods: T-cells populations from whole blood samples were analyzed by multicolour flow-cytometry in patients with stable CLL (n=10), progressive CLL (n=10) and patients in clinical response under Ibrutinib treatment (n=10) [(median time on treatment 2.06 years (0.69-4.37)]. Healthy donors’ values were used as reference. We further analysed the immunological synapses by coculturing in vitro autologous T-cells and CLL B-cells after stimulation, assessed by flow cytometry and Western Blot assays (CD3e and Granzyme B). Results: We observed an increase of CD4+:CD8+ ratio with a predominance of Th1 cells, decreased of Tregs and the expansion of effector memory CD8+ T-cells in stable and progressive CLL Furthermore, the terminally differentiated effector memory CD8+ T-cells re-expressing CD45RA (TEMRA) were significantly reduced in progressive CLL compared to stable CLL (5.60% vs.12.30%, p≤0.05). In sample patients under ibrutinib, however, CD4+:CD8+ ratio decreased and Th1:Th2 ratio increased due to Th1 polarization. In addition, the TEMRA cell population were normalized. We further observed that under ibrutinib the percentage of expression of PD1 significantly decreased mainly in CD4+ T-cells as compared to that seen in progressive CLL (Figure 1A). Interestingly, this observation was correlated with the fact that synapse capability was only partially recovered in CD4+ T-cells but not in CD8+ T-cells (Figure 1B). These changes resulted in an effective activation of TCR with an increased expression of CD3e and Granzyme B. Image:Summary/Conclusion: In conclusion, our results confirm that in CLL there is an imbalance of T-cell subpopulations (i.e CD4+:CD8+ ratio, Tregs, TEMRA,) and an anergic status which are more evident when the disease progresses. Treatment with ibrutinib may overcome T-cell dysfunction by not only controlling leukemic cells but also promoting antitumoral T-cell responses mediated by promoting Th1 polarization, restoring CD4+: B-cell interactions, and inducing CD8+ T-cells cytotoxicity.